Pressurized metered dose inhalers (pMDIs) are the most common vehicles for the delivery of drugs to the lungs, accounting for approximately 80% of total prescribed aerosols. However, the development of pMDI-based formulations has been confronted with several challenges since the replacement of chlorofluorocarbons (CFCs) with the more environmentally friendly hydrofluoroalkane (HFA) propellants. In spite of the fact that the operation of pMDIs with HFAs is similar to those containing CFCs, previous formulations are generally not compatible due to differences in physicochemical properties between these two classes of fluids.
Surface active agents (surfactants) are generally required excipients in both solution and dispersion formulations for valve lubrication and to provide stability to dispersed drug crystals. One of the issues in reformulating pMDIs with HFAs is related to the fact that hydrocarbon-based surfactants used in FDA-approved CFC formulations (oleic acid, sorbitan trioleate, and lecithin) have extremely low solubility in the more polar semi-fluorinated propellants. Accordingly, cosolvents have been generally employed in HFA-based formulations in order to enhance surfactant solubility. However, the presence of cosolvents in pMDIs can affect the vapor pressure of the propellant—thus affecting the size of the aerosol. Cosolvents can also negatively impact the chemical and physical stability of the formulations.
CFC-based dispersions of salbutamol (base) have been extensively employed in the treatment of asthma. Oleic acid was typically used as a dispersing agent and as a valve lubricant in CFC-based pMDIs. However, oleic acid is not compatible with HFAs. While the solubility of oleic acid can be enhanced in the semifluorinated propellants upon the addition of ethanol, such an approach is not always suitable. This restriction is related to the fact that salbutamol has an appreciable solubility in ethanol, and the presence of the cosolvent decreases the chemical stability of the formulation. Therefore, the salt of salbutamol, salbutamol sulfate, which has low solubility in ethanol, is currently being used in HFA-based pMDI formulations.
The discussion above illustrates the challenges in reformulating pMDIs with HFA-based propellants. In light of such difficulties, the development of novel amphiphiles (chemical compounds having both hydrophilic and lipophilic properties) for HFA-based suspensions has been fairly limited. This can be attributed, at least in part, to challenges in obtaining United States Food & Drug Administration (FDA) approval for new excipients. On the other hand, difficulties associated with studying the colloidal/interfacial properties of such systems in situ, and a lack of a fundamental understanding of solvation forces in semifluorinated solvents, have also hindered the development of new amphiphiles for HFA suspensions.
Colloidal probe microscopy (CPM) is a powerful technique for the screening of surface-active agents for colloidal suspensions. CPM is an atomic force microscopy (AFM)-based technique where the force of interaction between a colloidal particle attached to an AFM tip and another particle/substrate of interest is measured with high resolution. CPM has been widely used to investigate the effect of surfactants and other polymers on the interaction forces between colloidal particles in aqueous phase as well as in nonaqueous media. CPM has also been used to characterize the cohesive/adhesive force between particles of relevance in the pharmaceutical industry. In the context of inhalation therapy, the CPM literature has focused primarily on dry powder formulations. CPM has also been applied to a few systems of relevance to pMDIs, including the study of the ability of poly-(ethylene glycol) (PEG) and polyvinylpyrrolidone (PVP) to screen the cohesive forces of drug particles in 2H,3H perfluoropentane (HPFP), a mimicking solvent to propellant HFA, and the adhesive forces between drug particles and the walls of pMDI canisters.